Genetic factors contribute significantly to the risk of cocaine abuse in humans. However, the potential role of epigenetic influences on addiction phenotypes remains unclear. A growing body of evidence indicates that environmental information can be inherited. Thus, epigenetic changes in the mammalian germline can act as a transgenerational carrier of environmental perturbations. Here, we describe a rat model developed in order to delineate a heritable phenotype resulting from the self-administration of cocaine. We found that while the male offspring of cocaine-experienced sires (BCocSired) had delayed acquisition and reduced maintenance of cocaine self-administration relative to the offspring of yoked saline controls (BSalSired), there was no difference in the acquisition of cocaine self-administration in female offspring. These novel results suggest that cocaine experienced sires confer a resistance to cocaine reinforcement in their male offspring. The specific aims outlined in this application will assess specific mechanisms that may underlie this paternally transmitted phenotype associated with cocaine self-administration. The experiments in Specific Aim 1 are designed to assess epigenetic and behavioral mechanisms through which paternal cocaine self-administration may influence the behavior of their descendants. In Specific Aim 2 we will evaluate the acquisition of cocaine and food self-administration in the offspring (F1) and grand offspring (F2) of male rats that self-administered cocaine. Specific Aim 3 focuses on the potential role of medial prefrontal cortical brain-derived neurotrophic factor in the acquisition of cocaine self-administration in F1 and F2 CocSired rats. The preliminary data described in this application are novel and establish the inheritance of an addiction-related phenotype using an animal model. Our finding that the cocaine self-administration is reduced in BCocSired relative to BSalSired rats is robust and has significant implications in terms of human health. The next step is to determine the cellular and molecular mechanisms underlying this phenotype. The experiments described in this application will use state-of-the-art cellular, molecular and behavioral methodologies to i) examine epigenetic and behavioral mechanisms whereby cocaine-associated information can be transmitted from sires to offspring, ii) determine if the inherited cocaine resistance phenotype is transgenerational, and iii) assess specific neuronal mechanisms that may underlie this paternally transmitted phenotype associated with cocaine self- administration. PUBLIC HEALTH RELEVANCE: A growing body of evidence indicates that environmental information can be inherited, which suggests that changes in the mammalian germline can act as a trans-generational carrier of environmental information. Here, we describe a rat model developed in order to delineate heritable behavioral characteristics resulting from the self-administration of cocaine. Our results suggest that cocaine experienced sires confer a resistance to cocaine reinforcement in their male offspring. The experiments described in this application will use state-of- the-art cellular, molecular and behavioral methodologies to examine the mechanisms whereby cocaine- associated information can be transmitted from sires to offspring and assess specific neuronal changes that may underlie this paternally transmitted phenotype associated with cocaine self-administration.